RESUMEN

Ficolin-2 is regarded as an important innate immunity factor endowed with both lectin (carbohydrate recognition) qualities and ability to induce complement activation. The aim of this study was to investigate the association of the FCN2 3'-untranslated region (3'UTR) polymorphisms with ficolin-2 expression and perinatal complications in preterm neonates. The sequencing analysis allowed us to identify six 3'UTR polymorphisms with minor allele frequency (MAF) >1%: rs4521835, rs73664188, rs11103564, rs11103565, rs6537958 and rs6537959. Except for rs4521835, all adhered to Hardy-Weinberg expectations. Moreover, rs6537958 and rs6537959 were shown to be in perfect linkage disequilibrium (LD) with nine other genetic polymorphisms: rs7040372, rs7046516, rs747422, rs7847431, rs6537957, rs6537960, rs6537962, rs11462298 and rs7860507 together stretched on a distance of 1242 bp and very high LD with rs11103565. The 3'UTR region was shown to bind nuclear extract proteins. The polymorphisms at rs4521835 and rs73664188 were found to influence serum ficolin-2 concentration significantly. All polymorphisms identified create (together with exon 8 polymorphism, rs7851696) two haplotype blocks. Among 49 diplotypes (D1-D49) created from rs7851696 (G>T), rs4521835 (T>G), rs73664188 (T>C), rs11103564 (T>C), rs11103565 (G>A) and rs6537959 (T>A), twenty two occurred with frequency >1%. Two diplotypes: D13 (GTTTGT/GGTCGT) and D10 (GTTTGT/GGTCGA), were significantly more frequent among preterm neonates with early onset of infection and pneumonia, compared with newborns with no infectious complications (OR 2.69 and 2.81, respectively; both p<0.05). The minor (C) allele at rs73664188 was associated with an increased risk of very low (≤1500 g) birthweight (OR=1.95, p=0.042) but was associated with the opposite effect at rs11103564 (OR=0.11, p=0.005).

Asunto(s)

Regiones no Traducidas 3'/genética , Genotipo , Recien Nacido Prematuro , Infecciones/genética , Lectinas/genética , Neumonía/genética , Activación de Complemento , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Inmunidad Innata , Recién Nacido , Lectinas/sangre , Lectinas/metabolismo , Desequilibrio de Ligamiento , Masculino , Polimorfismo de Nucleótido Simple , Ficolinas

RESUMEN

PURPOSE: Hyperreflective foci (HRF) are OCT biomarkers for the progression of nonneovascular age-related macular degeneration (AMD) attributed to anteriorly migrated retinal pigment epithelial cells. We examined associations between rod- and cone-mediated vision and HRF plus smaller hyperreflective specks (HRS); we identified a histologic candidate for HRS. DESIGN: Cross-sectional study and histologic survey. PARTICIPANTS: Patients with healthy maculae (n = 34), early AMD (n = 26), and intermediate AMD (n = 41). METHODS: AMD severity was determined by color fundus photography. In OCT scans, HRF and HRS were counted manually. Vision tests probed cones (best-corrected visual acuity [VA], contrast sensitivity), mixed cones and rods (low-luminance VA, low-luminance deficit, mesopic light sensitivity), or rods (scotopic light sensitivity, rod-mediated dark adaptation [RMDA]). An online AMD histopathologic resource was reviewed. MAIN OUTCOME MEASURES: Vision in eyes assessed for HRF and HRS; histologic candidate for HRS. RESULTS: In 101 eyes of 101 patients, HRF and HRS were identified in 25 and 95 eyes, respectively, with good reliability. Hyperreflective foci were present but sparse in healthy eyes, infrequent in early AMD eyes, and frequent but highly variable among intermediate AMD eyes (mean±standard deviation [SD] number per eye, 0.1 ± 0.2, 0.2 ± 0.5, and 1.9 ± 3.4 for healthy, early AMD, and intermediate AMD eyes, respectively). Hyperreflective specks outnumbered HRF in all groups (mean±SD, 4.5 ± 3.2, 6.3 ± 5.8, and 19.4 ± 22.4, respectively). Delayed RMDA was associated strongly with more HRF and HRS (P < 0.0001). Hyperreflective foci also were associated with worse low-luminance VA (P = 0.0117). Hyperreflective specks were associated with worse contrast sensitivity (P = 0.0278), low-luminance VA (P = 0.0010), low-luminance deficit (P = 0.0031), and mesopic (P = 0.0018) and scotopic (P < 0.0001) sensitivity. By histologic analysis, cone lipofuscin was found in outer retinal layers of 25% of healthy aged eyes. CONCLUSIONS: Hyperreflective foci and HRS are markers of cellular activity associated with visual dysfunction, especially delayed RMDA, an AMD risk indicator assessing efficiency of retinoid resupply. Hyperreflective specks may represent lipofuscin translocating inwardly within cones. HRF and HRS may serve as structural end points in clinical trials targeting AMD stages earlier than atrophy expansion. These results should be confirmed in a larger sample.

Asunto(s)

Adaptación a la Oscuridad/fisiología , Epitelio Pigmentado de la Retina/patología , Células Fotorreceptoras Retinianas Bastones/fisiología , Degeneración Macular Húmeda/fisiopatología , Anciano , Anciano de 80 o más Años , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Epitelio Pigmentado de la Retina/fisiopatología , Tomografía de Coherencia Óptica/métodos , Degeneración Macular Húmeda/diagnóstico

RESUMEN

PURPOSE: To summarize the case of a 13 year-old boy diagnosed with a BRAO secondary to B. henselae infection. OBSERVATIONS: The patient presented with a sudden, unilateral, and painless scotoma. Fundoscopic findings and multimodal imaging were consistent with a BRAO with associated areas of intraretinal whitening along the involved artery. Upon further questioning, the patient reported having 15 cats at home. Antibodies were positive for B. henselae. The patient was treated with oral doxycycline 100 mg twice daily for 2 months with complete resolution of the retinal findings and the scotoma. CONCLUSIONS AND IMPORTANCE: B. henselae should be considered as a potential cause of retinitis and BRAO, even in pediatric-aged patients.

RESUMEN

PURPOSE: To describe the first known case of Bacteroides spp. related blebitis, keratitis, and endophthalmitis following uncomplicated trabeculectomy. METHODS: This was a case report and literature review. CASE: A 63-year-old immunocompetent white male underwent uncomplicated trabeculectomy of his right eye. Two weeks later, a blebitis with adjacent keratitis was diagnosed, progressing over several days to endophthalmitis despite hourly topical fortified antibiotic therapy. Although gram stain and culture of the bleb surface, a conjunctival suture, the aqueous humor, and the vitreous were negative, topical real-time quantitative polymerase chain reaction testing disclosed the presence of Bacteroides spp. Following treatment with topical and intravitreal clindamycin and intravenous meropenem, all clinical evidence of infection resolved. Best spectacle-corrected visual acuity improved to 20/25 (0.8) subsequent to combined cataract extraction, intraocular lens implantation, and pars plana vitrectomy for persistent vitreous debris. CONCLUSIONS: Bacteroides may be a rare cause of postoperative blebitis, keratitis, and endophthalmitis. A favorable outcome may be attained, provided that an accurate diagnosis and effective treatment can be provided, which may be facilitated by real-time quantitative polymerase chain reaction in select cases.

Asunto(s)

Infecciones por Bacteroides/microbiología , Bacteroides/aislamiento & purificación , Úlcera de la Córnea/microbiología , Endoftalmitis/microbiología , Infecciones Bacterianas del Ojo/microbiología , Trabeculectomía , Administración Oftálmica , Antibacterianos/uso terapéutico , Infecciones por Bacteroides/diagnóstico , Infecciones por Bacteroides/tratamiento farmacológico , Clindamicina/uso terapéutico , Úlcera de la Córnea/diagnóstico , Úlcera de la Córnea/tratamiento farmacológico , Quimioterapia Combinada , Endoftalmitis/diagnóstico , Endoftalmitis/tratamiento farmacológico , Infecciones Bacterianas del Ojo/diagnóstico , Infecciones Bacterianas del Ojo/tratamiento farmacológico , Glaucoma de Ángulo Abierto/cirugía , Humanos , Inyecciones Intravenosas , Inyecciones Intravítreas , Masculino , Meropenem/uso terapéutico , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa

RESUMEN

BACKGROUND: Pulmonary arterial hypertension is a chronic disease associated with poor long-term outcomes. Identifying predictors of long-term outcome in pulmonary arterial hypertension is important to assess disease severity and guide treatment. We investigate associations between efficacy parameters and long-term outcomes in patients with pulmonary arterial hypertension receiving riociguat in the PATENT-2 study. We also present safety and efficacy data from the final data cutoff of PATENT-2, where most patients had received at least 2 years of riociguat treatment. METHODS: Eligible patients from the PATENT-1 study entered the PATENT-2 open-label extension, which will continue until all patients transition to the commercial drug. All patients received riociguat individually adjusted to a maximum dose of 2·5 mg three times a day. The primary endpoint was safety and tolerability, assessed with recording adverse events, serious adverse events, discontinuations, and deaths; exploratory assessments included 6-min walking distance (6MWD), WHO functional class, N-terminal prohormone of brain natriuretic peptide (NT-proBNP)concentrations, Borg dyspnoea score, health-related quality of life (EQ-5D score), survival, and clinical worsening-free survival. Association between efficacy parameters and long-term outcomes was assessed using Kaplan-Meier analyses and a Cox proportional-hazards regression model. PATENT-2 is registered at ClinicalTrials.gov, number NCT00863681. FINDINGS: 396 patients entered PATENT-2, of whom 197 patients were receiving riociguat monotherapy and 199 were receiving riociguat in combination with endothelin receptor antagonists or prostanoids, or both. A significant association was noted between 6MWD, NT-proBNP concentration, and WHO functional class and overall survival at baseline (p=0·0006, 0·0225, and 0·0191, respectively), and at follow-up (p=0·021, 0·0056, and 0·0048, respectively). Riociguat was well tolerated in PATENT-2. Serious adverse events were recorded in 238 (60%) of the total population, and 45 (11%) patients discontinued treatment because of an adverse event. Improvements in 6MWD, WHO functional class, and NT-proBNP concentrations were maintained after 2 years of treatment. INTERPRETATION: These results support the long-term use of riociguat in patients with pulmonary arterial hypertension, and emphasise the prognostic value of 6MWD, WHO functional class, and NT-proBNP concentrations. FUNDING: Bayer Pharma AG.

Asunto(s)

Antihipertensivos/administración & dosificación , Hipertensión Pulmonar/tratamiento farmacológico , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Tiempo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Antagonistas de los Receptores de Endotelina/administración & dosificación , Femenino , Humanos , Hipertensión Pulmonar/sangre , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Prostaglandinas/administración & dosificación , Arteria Pulmonar , Calidad de Vida , Resultado del Tratamiento , Adulto Joven

RESUMEN

Virologic surveillance is essential to the success of the World Health Organization initiative to eradicate poliomyelitis. Molecular methods have been used to detect polioviruses in tissue culture isolates derived from stool samples obtained through surveillance for acute flaccid paralysis. This chapter describes the use of realtime PCR assays to identify and serotype polioviruses. In particular, a degenerate, inosine-containing, panpoliovirus (panPV) PCR primer set is used to distinguish polioviruses from NPEVs. The high degree of nucleotide sequence diversity among polioviruses presents a challenge to the systematic design of nucleic acid-based reagents. To accommodate the wide variability and rapid evolution of poliovirus genomes, degenerate codon positions on the template were matched to mixed-base or deoxyinosine residues on both the primers and the TaqMan™ probes. Additional assays distinguish between Sabin vaccine strains and non-Sabin strains. This chapter also describes the use of generic poliovirus specific primers, along with degenerate and inosine-containing primers, for routine VP1 sequencing of poliovirus isolates. These primers, along with nondegenerate serotype-specific Sabin primers, can also be used to sequence individual polioviruses in mixtures.

Asunto(s)

Poliomielitis/diagnóstico , Poliovirus/genética , ARN Viral/genética , Secuencia de Bases , Humanos , Poliomielitis/virología , Poliovirus/clasificación , Poliovirus/aislamiento & purificación , Reacción en Cadena de la Polimerasa/métodos , ARN Viral/aislamiento & purificación , Análisis de Secuencia de ARN/métodos

RESUMEN

Infections are a major cause of childhood mortality. We investigated components of the lectin pathway of complement activation in the context of sepsis at both genetic and protein levels in neonates, infants and older children. Major components of the lectin pathway and two genes for Toll-like receptors were studied in 87 neonates with confirmed sepsis and compared with 40 babies with infections who did not develop sepsis (disease controls) and 273 infection-free neonatal controls. A second cohort comprised 47 older children with sepsis and 87 controls. Low MBL-conferring genotypes (LXA/O+O/O) were more frequent in sepsis patients than in healthy controls but no significant differences in the frequency of SNPs of other lectin pathway genes (FCN1, FCN2, FCN3, MASP1/3, MASP2) or TLR receptor genes (TLR2, TLR4) were found. One case of primary MASP-2 deficiency was found among healthy pre-terms and one neonate suffering from SIRS was heterozygous for the rare FCN1 gene mutation, +6658 G>A. Generally, sepsis was associated with low serum MBL and low ficolin-2 concentrations on admission. Among neonates, ficolin-1 and MASP-2 levels were elevated in sepsis relative to healthy, but not disease, controls. Unlike neonates, ficolin-3 and MASP-2 levels were lower in older patients than in healthy controls while no difference was found for ficolin-1. With the possible exception of MBL, inherited lectin pathway insufficiencies do not seem to predispose to sepsis, rather changes in protein concentrations reflect alterations in disease course.

Asunto(s)

Lectina de Unión a Manosa de la Vía del Complemento/inmunología , Unidades de Cuidados Intensivos , Alelos , Infecciones Bacterianas/genética , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/microbiología , Infecciones Bacterianas/mortalidad , Estudios de Casos y Controles , Niño , Preescolar , Activación de Complemento , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Lactante , Lectinas/genética , Lectinas/metabolismo , Masculino , Lectina de Unión a Manosa/genética , Lectina de Unión a Manosa/inmunología , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/metabolismo , Mutación , Polimorfismo de Nucleótido Simple , Sepsis/genética , Sepsis/inmunología , Sepsis/microbiología , Sepsis/mortalidad , Ficolinas

Asunto(s)

Amianto , Exposición Profesional , Australia , Humanos , Mesotelioma , Enfermedades Profesionales

RESUMEN

Mycobacterium tuberculosis (TB) may utilise the lectin complement pathway to facilitate entry into its niche within macrophages. Previous studies examining mannose-binding lectin (MBL) in patients with TB have been limited by failure to correlate genotype/phenotype relationships. This study investigated serum levels and genotypes of MBL, Ficolin-2, Ficolin-3 and MASP-2 in 168 patients with pulmonary tuberculosis and 168 age/sex-matched controls. Low serum levels of MBL and Ficolin-2 were defined using cut-offs previously identified in the literature. Median MBL serum levels were higher in TB patients than controls-1400 ng/ml (IQR 435-2520) vs 1030 ng/ml (350-2050), p = 0.02-but this was not mirrored by a difference in MBL haplotype frequencies (MBL deficient haplotypes were observed in 11.9 % of TB patients and 11.3 % of controls). Severe Ficolin-2 deficiency (<1200 ng/ml) was more frequent in TB than controls (7.1 vs 3.0 %, odds ratio 2.51 95 % CI 0.86-7.28, p = 0.1) but the difference was not statistically significant. No relationship between Ficolin-2, Ficolin-3 or MASP-2 genotypes or serum levels and TB were observed. No strong relationship between the lectin complement pathway and pulmonary tuberculosis was observed. Previous data linking high MBL serum levels with TB were likely due to an acute phase response rather than a true effect on disease susceptibility.

Asunto(s)

Lectina de Unión a Manosa de la Vía del Complemento/fisiología , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Susceptibilidad a Enfermedades/sangre , Susceptibilidad a Enfermedades/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tuberculosis Pulmonar/genética , Adulto Joven

RESUMEN

Laboratory diagnosis has played a critical role in the Global Polio Eradication Initiative since 1988, by isolating and identifying poliovirus (PV) from stool specimens by using cell culture as a highly sensitive system to detect PV. In the present study, we aimed to develop a molecular method to detect PV directly from stool extracts, with a high efficiency comparable to that of cell culture. We developed a method to efficiently amplify the entire capsid coding region of human enteroviruses (EVs) including PV. cDNAs of the entire capsid coding region (3.9 kb) were obtained from as few as 50 copies of PV genomes. PV was detected from the cDNAs with an improved PV-specific real-time reverse transcription-PCR system and nucleotide sequence analysis of the VP1 coding region. For assay validation, we analyzed 84 stool extracts that were positive for PV in cell culture and detected PV genomes from 100% of the extracts (84/84 samples) with this method in combination with a PV-specific extraction method. PV could be detected in 2/4 stool extract samples that were negative for PV in cell culture. In PV-positive samples, EV species C viruses were also detected with high frequency (27% [23/86 samples]). This method would be useful for direct detection of PV from stool extracts without using cell culture.

Asunto(s)

Proteínas de la Cápside/genética , Heces/virología , Poliomielitis/virología , Poliovirus/genética , Animales , Secuencia de Bases , Línea Celular , Humanos , Ratones , Datos de Secuencia Molecular , Sistemas de Lectura Abierta , Poliovirus/clasificación , Poliovirus/aislamiento & purificación , Reproducibilidad de los Resultados , Alineación de Secuencia , Análisis de Secuencia de ADN

Asunto(s)

Anticuerpos Antifosfolípidos/sangre , Síndrome Antifosfolípido/sangre , Activación de Complemento/genética , Glicoproteínas/sangre , Lectinas/sangre , Lectina de Unión a Manosa/sangre , Adulto , Anciano , Anticuerpos Antifosfolípidos/inmunología , Síndrome Antifosfolípido/genética , Síndrome Antifosfolípido/inmunología , Síndrome Antifosfolípido/patología , Complemento C3a/genética , Complemento C3a/inmunología , Factor B del Complemento/genética , Factor B del Complemento/inmunología , Femenino , Expresión Génica , Glicoproteínas/genética , Glicoproteínas/inmunología , Humanos , Lectinas/genética , Lectinas/inmunología , Masculino , Lectina de Unión a Manosa/genética , Lectina de Unión a Manosa/inmunología , Persona de Mediana Edad , Ficolinas

RESUMEN

Mannose binding lectin (MBL) and ficolins contribute to host defence through activation of the lectin pathway of complement. In this study, serum levels of ficolin-2 and MBL were determined in 276 patients with community-acquired pneumonia (CAP). MBL deficiency and ficolin-2 insufficiency were defined using previously validated cut-offs. No differences were observed in MBL or ficolin-2 between patients and controls. MBL-deficient patients (<500 ng/ml) were not at higher risk of 30-day mortality odds ratio (OR) 0.97 (0.38-2.48,p=0.9) or a composite outcome of mortality, mechanical ventilation, vasopressor support (MV/VS) or complications OR 0.89 (0.44-1.77, p=0.9). Although no significant relationship between ficolin-2 insufficiency and outcome was observed, very low ficolin-2 levels (<1,200 ng/ml) were associated with an OR 1.23 (0.15-10.1), p=0.6 for 30-day mortality, 3.05 (0.61-15.2, p=0.2) for MV/VS and OR 2.05 (0.52-8.1, p=0.2) for the composite outcome. Low serum levels of MBL and ficolin-2 are not associated with CAP susceptibility. The high frequency of ficolin-2 insufficiency in patients with severe CAP would justify a larger investigation of ficolin-2 as a modifier of CAP severity.

Asunto(s)

Hospitalización , Lectinas/sangre , Neumonía/sangre , Neumonía/diagnóstico , Adulto , Anciano , Biomarcadores/sangre , Estudios de Cohortes , Infecciones Comunitarias Adquiridas/sangre , Infecciones Comunitarias Adquiridas/diagnóstico , Femenino , Hospitalización/tendencias , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Ficolinas

RESUMEN

BACKGROUND: Therapeutic hypothermia (TH) is used to mitigate cerebral injury after an out of hospital cardiac arrest. There is a perceived risk of increased arrhythmias with temperatures lower than the current target of 32-34°C for TH. This study sought to develop and investigate the electrophysiological changes in a sheep model of systemic hypothermia regarding the susceptibility to ventricular arrhythmias. METHODS: Ten sheep underwent systemic hypothermia using a venous-venous extra-corporeal circuit whilst instrumented with a 12 lead ECG. An epicardial sock recorded potentials to 30°C (N=10) or 26°C (N=6). Activation times (AT) and Activation Recovery Intervals (ARI) were calculated using custom software. RESULTS: The AT and ARI were significantly prolonged with increased heterogeneity during hypothermia. This effect was most pronounced between normothermia and 34°C during sinus rhythm (SR). For ventricular pacing (VP) however heterogeneity continued to increase with progressive hypothermia. CONCLUSIONS: Hypothermia causes a significant increase in the heterogeneity of depolarisation and repolarisation. There is evidence to suggest that SR is protective with most of the increase in heterogeneity occurring with cooling to 34°C. This raises the possibility that the current target temperatures for therapeutic hypothermia may be safely lowered to provide a gain in cerebral protection.

Asunto(s)

Arritmias Cardíacas , Electrocardiografía , Hipotermia Inducida/efectos adversos , Animales , Arritmias Cardíacas/etiología , Arritmias Cardíacas/fisiopatología , Modelos Animales de Enfermedad , Paro Cardíaco/etiología , Paro Cardíaco/fisiopatología , Ovinos

RESUMEN

Ficolins constitute a group of lectins involved in innate immunity. L-Ficolin, H-ficolin, and M-ficolin are present in human serum. The human ficolins differ in carbohydrate-binding specificity, but they have in common the ability to recognize the acetyl group. L-Ficolin and H-ficolin are associated with serine proteases termed MASPs (MBL-associated serine proteases) and their truncated proteins, and the complexes (L/H-ficolin-MASP) activate the lectin pathway of complement upon binding to their ligands. Recombinant M-ficolin is also able to form a complex with MASP, resulting in complement activation. L-Ficolin and H-ficolin can be purified as a complex with MASP from serum by utilizing their binding specificities. These ficolin-MASP complexes have an ability to activate C4. Human ficolins are quantified by ELISA using specific antibodies or ligands.

Asunto(s)

Proteínas del Sistema Complemento/inmunología , Proteínas del Sistema Complemento/metabolismo , Lectinas/aislamiento & purificación , Lectinas/metabolismo , Activación de Complemento/inmunología , Ensayo de Inmunoadsorción Enzimática , Humanos , Lectinas/química , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/metabolismo , Ficolinas

RESUMEN

Vaccine-derived polioviruses (VDPVs) are associated with polio outbreaks and prolonged infections in individuals with primary immunodeficiencies. VDPV-specific PCR assays for each of the three Sabin oral poliovirus vaccine (OPV) strains were developed, targeting sequences within the VP1 capsid region that are selected for during replication of OPV in the human intestine. Over 2400 Sabin-related isolates and identified 755 VDPVs were screened. Sensitivity of all assays was 100%, while specificity was 100% for serotypes 1 and 3, and 76% for serotype 2. The assays permit rapid, sensitive identification of OPV-related viruses and flag programmatically important isolates for further characterization by genomic sequencing.

Asunto(s)

Técnicas de Diagnóstico Molecular/métodos , Poliomielitis/diagnóstico , Poliomielitis/virología , Vacunas contra Poliovirus/efectos adversos , Poliovirus/aislamiento & purificación , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Virología/métodos , Humanos , Poliovirus/genética , Vacunas contra Poliovirus/administración & dosificación , Sensibilidad y Especificidad , Factores de Tiempo

RESUMEN

Ficolins are serum pattern recognition molecules. They have opsonic properties and are able to activate complement via the lectin pathway. This paper reports investigations concerning ficolin-2 and ficolin-3 in ovarian cancer (OC). Their serum levels, single nucleotide polymorphisms of the corresponding FCN2 and FCN3 genes and specific mRNA expression in ovarian sections were investigated in 128 patients suffering from primary OC and 197 controls operated on for reasons other than malignancies. The latter consisted of two reference groups: those with benign tumours (n = 123) and those with normal ovaries (NO) (n = 74). Serum ficolin-2 and ficolin-3 concentrations were higher among patients with malignant disease when compared with either of the reference groups. A significant correlation between ficolin-2 and ficolin-3 concentrations was found, while no correlations with CA125 antigen or CRP were observed. No differences in the frequency of single nucleotide polymorphisms at sites -64, -4 (promoter), +6359, or +6424 (exon 8) (FCN2 gene) nor in the frame-shift mutation 1637delC (FCN3 gene) were found between investigated groups. In contrast to serum concentrations, the expression of FCN2 gene (reported for the first time in ovarian sections) was significantly lower in women with OC in comparison with patients with NO but not with benign ovarian tumours. In case of FCN3 gene, its expression levels in OC group inversely correlated with serum ficolin-3 and were lower in comparison with controls.

Asunto(s)

Glicoproteínas/sangre , Glicoproteínas/genética , Lectinas/sangre , Lectinas/genética , Neoplasias Ováricas/sangre , Neoplasias Ováricas/genética , Adulto , Anciano , Anciano de 80 o más Años , Ensayo de Inmunoadsorción Enzimática , Femenino , Regulación Neoplásica de la Expresión Génica , Frecuencia de los Genes , Genotipo , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Polimorfismo de Nucleótido Simple , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto Joven , Ficolinas

RESUMEN

The human FCN2 gene codes for ficolin-2 (L-ficolin), a major pattern recognition molecule and activator of the lectin pathway of complement. Seven single nucleotide polymorphisms of this gene were investigated in a large series of cord blood DNA samples. Mutations from the majority to the minority alleles at -602, -4 and +6359 were associated with an increase, while mutations at -986, -557, -64 and +6424 were associated with a decrease, in protein concentration. Full (7 loci) genotypes were obtained for 1229 unrelated neonates, 12 sets of twin siblings and one set of triplets. Forty-four separate genotypes were detected. Four genotypes accounted for more than half the unrelated neonates, and >90% had one of the 12 commonest genotypes. Genotypes were associated with significant differences in mean serum ficolin-2, but the intra-genotype concentration ranges were large and greater than the inter-genotype differences. Consequently, there were no associations between genotypes and low birthweight babies or perinatal infections, and only a weak relationship with preterm deliveries, despite all three adverse pregnancy features being significantly associated with serum ficolin-2 protein. FCN2 genotyping may be of value in clinical studies, but not as a substitute for total serum ficolin-2 protein measurement.

Asunto(s)

Infecciones/genética , Lectinas/sangre , Lectinas/genética , Nacimiento Prematuro/genética , Lectina de Unión a Manosa de la Vía del Complemento/genética , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Recién Nacido , Infecciones/diagnóstico , Trabajo de Parto/genética , Polimorfismo de Nucleótido Simple , Embarazo , Nacimiento Prematuro/diagnóstico , Trillizos , Gemelos , Ficolinas

RESUMEN

Since 2005, a large poliomyelitis outbreak associated with type 2 circulating vaccine-derived poliovirus (cVDPV2) has occurred in northern Nigeria, where immunization coverage with trivalent oral poliovirus vaccine (tOPV) has been low. Phylogenetic analysis of P1/capsid region sequences of isolates from each of the 403 cases reported in 2005 to 2011 resolved the outbreak into 23 independent type 2 vaccine-derived poliovirus (VDPV2) emergences, at least 7 of which established circulating lineage groups. Virus from one emergence (lineage group 2005-8; 361 isolates) was estimated to have circulated for over 6 years. The population of the major cVDPV2 lineage group expanded rapidly in early 2009, fell sharply after two tOPV rounds in mid-2009, and gradually expanded again through 2011. The two major determinants of attenuation of the Sabin 2 oral poliovirus vaccine strain (A481 in the 5'-untranslated region [5'-UTR] and VP1-Ile143) had been replaced in all VDPV2 isolates; most A481 5'-UTR replacements occurred by recombination with other enteroviruses. cVDPV2 isolates representing different lineage groups had biological properties indistinguishable from those of wild polioviruses, including efficient growth in neuron-derived HEK293 cells, the capacity to cause paralytic disease in both humans and PVR-Tg21 transgenic mice, loss of the temperature-sensitive phenotype, and the capacity for sustained person-to-person transmission. We estimate from the poliomyelitis case count and the paralytic case-to-infection ratio for type 2 wild poliovirus infections that ∼700,000 cVDPV2 infections have occurred during the outbreak. The detection of multiple concurrent cVDPV2 outbreaks in northern Nigeria highlights the risks of cVDPV emergence accompanying tOPV use at low rates of coverage in developing countries.

Asunto(s)

Poliomielitis/epidemiología , Vacuna Antipolio Oral/efectos adversos , Vacunas contra Poliovirus/efectos adversos , Poliovirus/fisiología , Animales , Proteínas de la Cápside/genética , Proteínas de la Cápside/inmunología , Brotes de Enfermedades , Femenino , Humanos , Masculino , Ratones , Datos de Secuencia Molecular , Nigeria/epidemiología , Filogenia , Poliomielitis/virología , Poliovirus/clasificación , Poliovirus/genética , Poliovirus/inmunología , Vacuna Antipolio Oral/administración & dosificación , Vacunas contra Poliovirus/genética , Vacunas contra Poliovirus/inmunología

RESUMEN

BACKGROUND: Mannose-binding lectin (MBL) is a key component of innate immunity. MBL deficiency is common (10-30% of the general population depending on the definition used) and has been associated with disease progression in cystic fibrosis. We aimed to assess the effect of MBL deficiency on disease severity in non-cystic fibrosis bronchiectasis. METHODS: We recruited patients with non-cystic fibrosis bronchiectasis and age-matched and sex-matched controls at a specialist bronchiectasis clinic in Edinburgh, UK. We assessed MBL function with genotyping (low-expressing genotype [deficiency] defined as homozygosity for exon 1 mutations [YO/YO] or compound heterozygosity [XA/YO]; YA/YO and XA/XA genotypes were defined as intermediate-expressing with all other genotypes defined as high-expressing) and serum measurements (deficiency defined with two parameters: <500 ng/mL or <200 ng/mL). We assessed rates of exacerbation, chronic bacterial colonisation, and lung function during 4 years of follow-up. FINDINGS: We included 470 patients with bronchiectasis and 414 controls. MBL genotype frequencies and MBL serum concentrations did not differ between patients and controls. 55 (12%) patients with bronchiectasis had low-expressing genotypes. These patients had a mean of 2·7 exacerbations per year (SD 1·8), compared with 1·9 per year (1·2) for 135 patients with intermediate-expressing genotypes and 1·9 per year (1·3) for 280 patients with high-expressing genotypes (p<0·0001). Chronic colonisation with bacteria was most frequent in patients with low-expressing genotypes (47 [85%] patients vs 82 [61%] patients with intermediate-expressing genotypes and 183 [65%] patients with high-expressing genotypes; p=0·0041); especially P aeruginosa colonisation (19 [35%] patients vs 13 [10%] patients and 36 [13%] patients; p<0·0001). Patients with low-expressing genotypes were more likely to be admitted to hospital for severe exacerbations during follow-up (27 [49%] patients vs 42 [31%] patients and 87 [31%] patients; p=0·032). Patients with low-expressing genotypes also had increased scores for radiological severity and worse quality of life compared with the other two groups. MBL serum deficiency (<200 ng/mL) was associated with increased exacerbations, hospital admissions, and radiological severity. When <500 ng/mL was used as the definition of deficiency, the associations with exacerbation frequency and radiological severity were no longer significant. INTERPRETATION: MBL might be an important modifier of disease severity in non-CF bronchiectasis. FUNDING: UK Medical Research Council, UK Chief Scientists Office.

Asunto(s)

Bronquiectasia , Lectina de Unión a Manosa/deficiencia , Lectina de Unión a Manosa/genética , Errores Innatos del Metabolismo/complicaciones , Anciano , Carga Bacteriana , Bronquiectasia/diagnóstico , Bronquiectasia/epidemiología , Bronquiectasia/etiología , Bronquiectasia/genética , Bronquiectasia/fisiopatología , Progresión de la Enfermedad , Modificador del Efecto Epidemiológico , Femenino , Estudios de Asociación Genética , Pruebas Genéticas , Humanos , Inmunidad Innata/genética , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proyectos de Investigación , Pruebas de Función Respiratoria/métodos , Índice de Severidad de la Enfermedad , Reino Unido/epidemiología

RESUMEN

A rare cause of ST-segment elevation mimicking myocardial infarction has been reported in the setting of acute pneumothorax. We present a middle-aged woman with a right-sided secondary pneumothorax who developed severe chest pain associated with ST-segment elevation suggestive of acute myocardial infarction. Symptoms resolved immediately after advancement of the dislodged chest drain. A subsequent coronary angiogram was normal. This case highlights an uncommon electrocardiographic alteration and discusses possible pathophysiological mechanisms.

Asunto(s)

Dolor en el Pecho/etiología , Neumotórax/terapia , Dolor en el Pecho/diagnóstico , Tubos Torácicos , Drenaje , Electrocardiografía , Femenino , Humanos , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico , Neumotórax/complicaciones